DESCRIPTION: The availability of highly active antiretroviral therapies (HAART), including the HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), has prolonged survival and improved quality of life for individuals with HIV infection and AIDS. Nonetheless treatment of comorbid psychiatric illness and substance abuse in HIV-infected patients is greatly complicated by drug interactions with HAART components. Many HAART agents are inhibitors and/or inducers of human Cytochrome P450 3A (CYP3A) isoforms, responsible for metabolism of many psychotropic drugs, potentially abusable drugs, and substance abuse treatments. HAART agents may also inhibit and/or induce activity of P-glycoprotein (P-gp), a transport protein involved in gastrointestinal bioavailability and CNS entry of a number of drugs and foreign chemicals. HAART components, through their actions on CYP3A or P-gp, may: a) Reduce efficacy, enhance toxicity, or enhance abusability of legitimately prescribed psychotropic drugs; b) Increase toxicity of illegal drugs of abuse; c) Reduce efficacy or increase toxicity of agents used to treat substance abuse. We propose a coordinated series of clinical, experimental, in vitro and cell culture studies designed to develop a paradigm whereby the mechanisms and consequences of these interactions can be expeditiously evaluated, with the ultimate objective of developing predictive schemes based on experimental and in vitro models. Clinical studies have the objective of developing and validating a probe approach for simultaneous quantitation of CYP3A (using midazolam) and P-gp activity (using fexofenadine) in human subjects; subsequently the method is applied to assessing CYP3A and P-gp inhibition and induction with initial and extended exposure to ritonavir, delavirdine, and nevirapine. Cell culture models will assess P-gp mediated transport of various psychotropic drugs, potentially abusable drugs, and substance abuse treatments, as well as regulation of P-gp expression by extended exposure to HAART components, and to agents pertinent to substance abuse. The development and validation of these models should lead to more expeditious testing of interactions with HAART compounds, and ultimately safer and more effective treatment of comorbid substance abuse disorders or psychiatric illness in HIV-infected individuals.